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Synlett 2004(5): 0773-0778  
DOI: 10.1055/s-2004-817778
LETTER
© Georg Thieme Verlag Stuttgart · New York

Parallel Solid Phase Synthesis of Tricomponent Bisubstrate Analogues as Potential Fucosyltransferase Inhibitors

Dmitri V. Filippova, Hans van den Elsta, Cornelia M. Trompb, Gijs A. van der Marela, Constant A. A. van Boeckelb, Herman S. Overkleeft*a, Jacques H. van Boom*a
a Leiden Institute of Chemistry, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands
Fax: +31(71)5274307; e-Mail: j.boom@chem.leidenuniv.nl;
b Department of Medicinal Chemistry, N. V. Organon, P. O. Box 20, 5340 BH Oss, The Netherlands
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Publication History

Received 11 December 2003
Publication Date:
10 February 2004 (online)

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Abstract

A combinatorial library of 32 tricomponent bisubstrate fucosyltransferase analogs has been generated using solid-phase peptide synthesis with orthogonally protected lysine as a scaffold.

Key words

nucleosides - solid-phase synthesis - glycopeptides - combinatorial chemistry - substrate analogs

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Earlier (see ref. [5] ) we called these compounds ‘trisubstrate analogues’, as opposed to the bisubstrate analogues earlier reported by Hindsgaul and coworkers (see ref. [4a] ). Later on similar compounds were termed ‘tricomponent bisubstrate analogues’ on the basis that glycosyltransferases employ two, instead of three, substrates (see also ref. [4e] ).

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Compound Ia: 1H NMR (600 MHz, D2O): δ = 7.89 (s 1 H), 5.84 (d, 1 H, J = 5.5 Hz), 4.51 (d, 1 H, J = 8.4 Hz), 4.37-4.20 (m, 8 H), 3.97 (AB, 2 H), 3.87 (d, 1 H, J = 12 Hz), 3.72 (m, 4 H), 3.62-3.52 (m, 5 H), 3.43 (m, 2 H), 3.08 (br m, 2 H), 2.01 (s, 3 H), 1.61 (br m, 2 H), 1.40 (br m, 2 H), 1.25 (br m, 2 H), 1.21 (d, 3 H, J = 6.2 Hz). ESI-MS: 933.5 [M + H+]. Compound IVb: 1H NMR (600 MHz, D2O): δ = 7.87 (s 1 H), 5.84 (d, 1 H, J = 5.6 Hz), 4.51 (d, 1 H, J = 8.4 Hz), 4.28-4.12 (m, 5 H), 3.86 (d, 1 H, J = 11.5 Hz), 3.76-3.70 (m, 4 H), 3.63 (m, 4 H), 3.53 (m, 2 H), 3.43 (m, 2 H), 3.08 (br t, 2 H), 2.00 (s, 3 H), 1.65 (br m, 2 H), 1.41 (br. m, 2 H), 1.21 (br. m, 2 H), 1.14 (d, 3 H, J = 6.4 Hz). ESI-MS: 846.6 [M + H+]. Compound Va: 1H NMR (600 MHz, D2O) δ = 7.89 (s, 1 H), 5.84 (d, 1 H, J = 5.6 Hz), 4.54 (d, 1 H, J = 8.4 Hz), 4.34 (m, 2 H), 4.26 (m, 2 H), 4.18 (m, 4 H), 3.96 (m, 2 H), 3.86 (m, 1 H), 3.73 (m, 4 H), 3.62 (m, 2 H), 3.53 (m, 3 H), 3.44 (m, 2 H), 3.15-3.00 (m, 2 H), 2.00 (s, 3 H), 1.61 (br m, 2 H), 1.39 (br m, 2 H), 1.25 (br m, 2 H), 1.20 (d, 3 H, J = 6.2 Hz). ESI-MS: 933.4 [M + H+]. Compound Vb: 1H NMR (600 MHz, D2O) δ = 7.89 (s, 1 H), 5.83 (d, 1 H, J = 5.6 Hz), 4.54 (d, 1 H, J = 8.4 Hz), 4.34-4.18 (m, 5 H), 3.99-3.86 (m, 3 H), 3.76-3.43 (m, 12 H), 3.11 (br m, 2 H), 1.99 (s, 3 H), 1.62 (br m, 2 H), 1.39 (br m, 2 H), 1.25 (br m, 2 H), 1.21 (d, 3 H, J = 6.2 Hz). ESI-MS: 903.4 [M + H+].

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Compound 16 (a 1:3 mixture of 2′-en-3′-O-acetates, chemical shifts are given for the major isomer): 1H NMR (200 MHz, CDCl3): δ = 7.80 (s, 1 H, H-8), 7.11 (m, 2 H, Pac), 6.81 (m, 3 H, Pac), 5.87 (d, 1 H, J 12 = 4.8 Hz, H-1′), 5.75 (dd, 1 H, J 21 = 4.8 Hz, J 23 = 5.7 Hz, H-2′), 5.49 (t, 1 H, J 32 = 5.7 Hz, H-3′), 4.58 (s, 2 H, CH2O), 4.42 (br s, 2 H, 2 NH), 4.14 (m, 1 H, H-4′), 3.46 (ABX, 2 H, H-5′), 2.42 (m, 4 H, CH2, succinyl), 1.95 (s, 3 H, acetyl). 13C NMR (50 MHz, CDCl3): δ = 173.7, 170.9, 170.4, 169.7 (C=O), 156.5, 155.2 (C6, Cq, Pac), 147.6, 146.6 (C4, C2), 138.0 (C-8), 129.2, 121.7 (Ct, Pac), 121.0 (C5), 114.2 (Ct, Pac), 86.4, 80.4, 72.5, 70.0 (C-1′, C-2′, C-3′, C-4′), 66.3 (CH2O, Pac), 50.7 (C-5′), 28.3 (CH2, succinyl), 19.9 (CH3, acetyl). ESI-MS: 607.2 [M + Na]+, negative mode: 583.2 [M - H]-, 482.9 [M - succinic anhydride - H]-.

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Protonated molecular ion of oxazoline 7 was consistently found in the ESI MS spectra of pure GlcNAc derivatives, probably due to the loss of the aglycon in the gas phase.